nejmoa050405

n engl j med

352;11

www.nejm.org march

17, 2005

1071

The

new englandjournal

of

medicine

established in 1812

march

17

,

2005

vol. 352 no. 11

Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention

Scott D. Solomon, M.D., John J.V. McMurray, M.D., Marc A. Pfeffer, M.D., Ph.D., Janet Wittes, Ph.D., Robert Fowler, M.S., Peter Finn, M.D., William F. Anderson, M.D., M.P.H., Ann Zauber, Ph.D.,

Ernest Hawk, M.D., M.P.H., and Monica Bertagnolli, M.D., for the Adenoma Prevention with Celecoxib (APC) Study Investigators*

abstract

From the Cardiovascular Division, Depart-ments of Medicine (S.D.S., M.A.P., P.F.)and Surgery (M.B.), Brigham and WomensHospital, Harvard Medical School, Boston;Western Infirmary, University of Glasgow,Glasgow, Scotland (J.J.V.M.); Statistics Col-laborative, Washington, D.C. (J.W., R.F.);National Cancer Institute, Bethesda, Md.(W.F.A., E.H.); and Memorial Sloan-Ketter-ing Cancer Center, New York (A.Z.). Addressreprint requests to Dr. Solomon at the Car-diovascular Division, Brigham and WomensHospital, 75 Francis St., Boston, MA 02115,or at [email protected].

*Participants in the APC study are listedin the Appendix.

This article was published at www.nejm.org on February 15, 2005.

N Engl J Med 2005;352:1071-80.

Copyright 2005 Massachusetts Medical Society.

background

Selective cyclooxygenase-2 (COX-2) inhibitors have come under scrutiny because of re-ports suggesting an increased cardiovascular risk associated with their use. Experimen-tal research suggesting that these drugs may contribute to a prothrombotic state pro-vides support for this concern.

methods

We reviewed all potentially serious cardiovascular events among 2035 patients with ahistory of colorectal neoplasia who were enrolled in a trial comparing two doses ofcelecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectaladenomas. All deaths were categorized as cardiovascular or noncardiovascular, andnonfatal cardiovascular events were categorized in a blinded fashion according to aprespecified scheme.

results

For all patients except those who died, 2.8 to 3.1 years of follow-up data were available.A composite cardiovascular end point of death from cardiovascular causes, myocardialinfarction, stroke, or heart failure was reached in 7 of 679 patients in the placebo group(1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twicedaily (2.3 percent; hazard ratio, 2.3; 95 percent confidence interval, 0.9 to 5.5) and with23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4 percent; hazard ratio,3.4; 95 percent confidence interval, 1.4 to 7.8). Similar trends were observed for othercomposite end points. On the basis of these observations, the data and safety monitor-ing board recommended early discontinuation of the study drug.

conclusions

Celecoxib use was associated with a dose-related increase in the composite end pointof death from cardiovascular causes, myocardial infarction, stroke, or heart failure. Inlight of recent reports of cardiovascular harm associated with treatment with otheragents in this class, these data provide further evidence that the use of COX-2 inhibitorsmay increase the risk of serious cardiovascular events.

The New England Journal of Medicine Downloaded from nejm.org on October 9, 2014. For personal use only. No other uses without permission.

Copyright 2005 Massachusetts Medical Society. All rights reserved.

n engl j med

352;11

www.nejm.org march

17

,

2005

The

new england journal

of

medicine

1072

he promise of a lower incidence

of gastrointestinal side effects with the useof selective cyclooxygenase-2 (COX-2) in-

hibitors than with the use of nonselective nonste-roidal antiinflammatory drugs (NSAIDs) or aspirinhas led to a marked increase in prescriptions forCOX-2 inhibitors, despite the fact that they offersimilar degrees of pain relief.

1-3

In addition, theidentification of COX-2 as a promoter of intestinaltumorigenesis suggested that inhibiting this en-zyme could prevent the formation of premalignantcolorectal adenomas.

4-8

Recently, however, this classof drugs has come under scrutiny because of clini-cal reports that they were associated with an in-creased risk of serious cardiovascular harm.

9-11

Themechanism of this effect is suggested in part by ev-idence that selective inhibition of COX-2 can blockthe production of prostacyclin without affectingthe synthesis of thromboxane A

2

,

10

thereby poten-tially creating a prothrombotic state.

The observation of an increased incidence ofdeath from cardiovascular causes, myocardial in-farction, or stroke among patients receiving rofe-coxib in the Adenomatous Polyp Prevention onVioxx (APPROVe) trial and the associated voluntarywithdrawal of this drug from the market promptedthe data and safety monitoring board and steeringcommittee of a similar ongoing trial of celecoxib torequest a focused reassessment of data on cardio-vascular safety by an independent committee, withthe results presented at their scheduled meeting onDecember 10, 2004. The study was a prospective,randomized, double-blind, multicenter trial assess-ing the efficacy of celecoxib for the prevention ofadenomatous polyps in patients who had under-gone endoscopic polypectomy. Because neitherprior clinical trials nor observational studies hadreported a clearly increased risk of cardiovascularevents with celecoxib use,

2,5,12-16

this longer-term,placebo-controlled trial provided an important op-portunity to evaluate the potential association. Thisreport describes the findings of the independentcardiovascular safety committee.

patients

The Adenoma Prevention with Celecoxib (APC)study compared the efficacy and safety of 200 mg ofcelecoxib twice daily, 400 mg of celecoxib twicedaily, and placebo in reducing the occurrence of ad-

enomatous polyps in the colon and rectum one yearand three years after endoscopic polypectomy. Thetrial was led by the Strang Cancer Prevention Cen-ter (New York) and cosponsored by the NationalCancer Institute and Pfizer. Ninety-one sites par-ticipated (72 in the United States, 1 in the UnitedKingdom, 8 in Australia, and 10 in Canada). Partici-pants ranged from 32 to 88 years of age and wereconsidered to have a clinically significant risk ofcolorectal adenoma on the basis of a history of ei-ther multiple adenomas or a single adenoma thatwas at least 0.5 cm in diameter. All known adeno-mas were removed colonoscopically before drugtreatment began.

A detailed medical history, including baseline as-sessment of cardiovascular disease status and riskfactors for cardiovascular disease, was obtained foreach patient. The protocol was reviewed and ap-proved by the appropriate institutional reviewboards, and all patients provided written informedconsent before enrollment. Patients were randomlyassigned to treatment with the use of a computer-generated randomization schedule. At the time ofdata review, 2035 patients had undergone random-ization in a double-blind manner at a 1:1:1 ratio,after stratification according to the use or nonuse ofaspirin for cardiovascular prophylaxis and the en-rolling center. Enrollment began in November 1999and concluded in March 2002. Compliance was as-sessed by means of both pill counts and standardmonitoring of medical records every 6 to 12 weeks.

review of cardiovascular safety

The cardiovascular safety committee developed end-point definitions as guidelines for adjudication. Thecommittee classified and adjudicated the end pointsby defining a hierarchy of composite end points(based on clinical importance and the prior findingswith rofecoxib). These guidelines were designedspecifically to assess cardiovascular safety (listedin the Supplementary Appendix, available with thefull text of this article at www.nejm.org). An initialreview identified all deaths and potential nonfatalcardiovascular adverse events. Two experienced in-dependent assessors reviewed these events usingmedical records and narratives supplied by site in-vestigators. Myocardial infarction was defined onthe basis of either a clinical presentation character-ized by typical symptoms, signs, or electrocardio-graphic changes associated with an elevation inthe level of a cardiac marker or angiographic evi-

t

methods



n engl j med

352;11

www.nejm.org march

17, 2005

celecoxib and cardiovascular risk

1073

dence of coronary thrombosis. Stroke was definedas a persistent focal neurologic event whose onsetwas sudden and was not due to trauma or a tumor.Other cardiovascular events were categorized ac-cording to a preplanned schema. When this initialdocumentation was insufficient for adjudication,additional information was obtained from the in-vestigative sites.

The entire cardiovascular safety committee wasunaware of the patients treatment assignmentsthroughout the review process. For the purposes ofthis analysis, we evaluated a hierarchy of compos-ite end points, including death from cardiovascularcauses, myocardial infarction, stroke, heart failure,unstable angina, and the need for a cardiovascularprocedure.

statistical analysis

Randomization codes were provided to StatisticsCollaborative (Washington, D.C.). All analyses wereperformed according to the intention-to-treat prin-ciple, with data on each patient analyzed accordingto the original randomized treatment assignment.Log-rank tests were used to compare the time to acardiovascular event in the three groups for eachcomposite end point of interest. Cox models, withthe treatment group as the only covariate, wereused to estimate hazard ratios for the two celecoxibgroups as compared with the placebo group. Al-though the randomization was stratified accordingto the baseline use or nonuse of aspirin and the cen-ter, the Cox models did not include these stratifyingvariables. Censoring was defined by assuming thata patient was followed for 37 months, until death,or until January 6, 2005 (the date defined for thisanalysis as the common close-out date) which-ever came first. At the time of this review, we hadfollow-up information for more than 97 percent ofthe patient-years at risk. Incidence rates were cal-culated for individual and composite cardiovascu-lar events by dividing the number of patients withevents by the number of patient-years at risk.

Important subgroups based on baseline charac-teristics were prespecified. To examine whether theeffect of celecoxib varied between subgroups, weconstructed Cox models with terms for treatment,subgroup, and the interaction between subgroupand treatment and evaluated the interaction termsfor statistical significance.

Recommendations to the studys data and safetymonitoring board were made on the basis of data

available at the time of the original analysis. Thisanalysis contains data on three additional cardio-vascular events that were not included in the origi-nal report.

At the time of the analysis, 77 percent of the 2035patients had completed the study, and all of the re-maining surviving patients had completed at least2.8 years of follow-up (range, 2.8 to 3.1). The base-line characteristics were similar among the threegroups (Table 1). The incidence of the prespecifiedcomposite cardiovascular end points, analyzed ac-cording to the time to the first event, and the asso-ciated hazard ratios are shown in Table 2. As com-pared with the placebo group, the group given 200mg of celecoxib twice daily had a hazard ratio fordeath from cardiovascular causes, myocardial in-farction, stroke, or heart failure of 2.3 (95 percentconfidence interval, 0.9 to 5.5), and the group re-ceiving 400 mg of celecoxib twice daily had a hazardratio of 3.4 (95 percent confidence interval, 1.4 to7.8). The results for the individual components ofthe composite end point are shown in Table 3.

There were six deaths in the placebo group, six inthe group given 200 mg of celecoxib twice daily, andnine in the group given 400 mg twice daily, and one,three, and six of the deaths, respectively, were dueto cardiovascular causes. The KaplanMeier curvesfor the combined end point of death from cardio-vascular causes, myocardial infarction, stroke, orheart failure in the three groups are shown in Fig-ure 1. The annualized incidence of death from car-diovascular causes, stroke, myocardial infarction, orheart failure was 3.4 events per 1000 patient-yearsin the placebo group, 7.8 events per 1000 patient-years in the group given 200 mg of celecoxib twicedaily, and 11.4 events per 1000 patient-years in thegroup given 400 mg twice daily.

In addition to the increased risk of the prespec-ified composite end point of cardiovascular events,the point estimate of the number of venous throm-boembolic events was also increased (though notsignificantly) among patients receiving celecoxib:four in the group given 400 mg of celecoxib twicedaily and three in the group given 200 mg twice dai-ly, as compared with one in the placebo group (haz-ard ratio for the two celecoxib groups combined,3.5; 95 percent confidence interval, 0.4 to 28.5).There was no apparent increase in the risk of un-

results



n engl j med

352;11

www.nejm.org march

17

,

2005

The

new england journal

of

medicine

1074

stable angina, arrhythmia, or the need for a cardio-vascular procedure. The hazard ratios associatedwith celecoxib use decreased when a broader classof cardiovascular events, including unstable angi-na and the need for a cardiovascular procedure,was added to the composite end point. The hazardratio associated with celecoxib was not significant-ly affected by any of the baseline characteristics ex-amined, including aspirin use at baseline (Table 4).

On December 16, 2004, on the basis of thesefindings, the advice of the cardiovascular safetycommittee, and previous findings with drugs in thesame class, the data and safety monitoring boardconcluded that continued exposure to celecoxibplaced patients at increased risk for serious cardio-vascular events. On the basis of this recommenda-tion, the steering committee stopped the use ofstudy medication among the patients remaining inthe trial. The trial remained blinded, and follow-upfor the end point of adenoma continued. Threeevents that were documented after the study wasstopped are included in the present analysis; theirinclusion does not alter the overall conclusions ofthe report issued on December 16, 2004.

In a large, randomized, placebo-controlled, double-blind, multicenter trial, we found that twice-daily

treatment with 200 or 400 mg of celecoxib to pre-vent colorectal adenomas led to a dose-related in-crease in the risk of serious cardiovascular events,including death from cardiovascular causes, myo-cardial infarction, stroke, and heart failure. Theseresults were consistent among the individual com-ponents of the composite end point. Because theuse of other selective COX-2 inhibitors, includingrofecoxib, valdecoxib, and parecoxib, has also beenassociated with an increased rate of cardiovascularevents,

17,18

our results heighten concern that thisclass of drug may be associated with increased car-diovascular risk. The cardiovascular safety commit-tee also completed a preliminary review of cardio-vascular safety in another study, the Prevention ofSpontaneous Adenomatous Polyps (PreSAP) trial,which randomly assigned patients with a history ofcolorectal adenomas to receive either 400 mg of cele-coxib once a day or placebo. The preliminary analy-sis did not show an increase in risk at this dose.

The reason for the apparent increase in cardio-vascular risk associated with the use of COX-2 in-hibitors is uncertain. One prominent hypothesisinvolves the effects of COX-2 inhibitors on twokey prostanoids, prostacyclin and thromboxaneA

2

, which have a crucial role in vascular homeo-stasis.

9,19,20

These prostanoids are generated bythe action of the cyclooxygenase-1 (COX-1) andCOX-2 isoenzymes on arachidonic acid.

21

Throm-

discussion

* Plusminus values are means SD. There were no significant differences among the groups.

Data were missing for one patient in the placebo group.

Table 1. Baseline Characteristics of the Patients.*

CharacteristicPlacebo(N=679)

Celecoxib, 200 mgTwice Daily (N=685)

Celecoxib, 400 mg Twice Daily (N=671)

Age yr 59.79.7 59.79.4 59.99.4

Male sex no. (%) 473 (69.7) 460 (67.2) 454 (67.7)

History of cardiovascular events no. (%) 321 (47.3) 335 (48.9) 307 (45.8)

Myocardial infarction 29 (4.3) 22 (3.2) 31 (4.6)

Cerebrovascular disease 14 (2.1) 20 (2.9) 13 (1.9)

Congestive heart failure 14 (2.1) 6 (0.9) 11 (1.6)

Angina 51 (7.5) 50 (7.3) 42 (6.3)

Hypertension 277 (40.8) 287 (41.9) 260 (38.7)

Diabetes no. (%) 61 (9.0) 66 (9.6) 64 (9.5)

Current smoker no. (%) 122 (18.0) 119 (17.4) 96 (14.3)

Aspirin use no. (%) 213 (31.4) 201 (29.3) 200 (29.8)

Use of lipid-lowering drug no. (%) 184 (27.1) 188 (27.4) 191 (28.5)



n engl j med

352;11

www.nejm.org march

17, 2005


1075

*M

I den

otes

myo

card

ial i

nfar

ctio

n.

Tabl

e 2.

Inci

denc

e of

and

Haz

ard

Rat

ios

for

the

Com

posi

te E

nd P

oint

s in

the

Cel

ecox

ib G

roup

s R

elat

ive

to th

e Pl

aceb

o G

roup

.

End

Poin

t*Pl

aceb

o (N

=679

)

Cel

ecox

ib,

200

mg

Twic

e D

aily

(N

=68

5)

Cel

ecox

ib,

400

mg

Twic

e D

aily

(N

=67

1)

Bot

h C

elec

oxib

G

roup

s (N

=13

56)

Plac

ebo

(N=

679)

Cel

ecox

ib,

200

mg

Twic

e D

aily

(N

=68

5)

Cel

ecox

ib,

400

mg

Twic

e D

aily

(N

=67

1)

Bot

h C

elec

oxib

G

roup

s (N

=13

56)

Cel

ecox

ib,

200

mg

Twic

e D

aily

(N

=68

5)

Cel

ecox

ib,

400

mg

Twic

e D

aily

(N

=67

1)

Bot

h C

elec

oxib

G

roup

s (N

=13

56)

num

ber o

f pat

ient

s (p

erce

nt)

rate

/100

0 pa

tient

-yea

rsha

zard

ratio

(95

% c

onfid

ence

inte

rval

)

Dea

th fr

om c

ardi

ovas

-cu

lar

caus

es1

(0.1

)3

(0.4

)6

(0.9

)9

(0.7

)0.

51.

42.

92.

23.

0 (0

.32

8.6)

6.1

(0.7

50.

3)4.

5 (0

.63

5.5)

Dea

th fr

om c

ardi

ovas

-cu

lar c

ause

s or

non

-fa

tal M

I

4 (0

.6)

12 (

1.8)

15 (

2.2)

27 (

2.0)

1.9

5.8

7.4

6.6

3.0

(1.0

9.3

)3.

8 (1

.31

1.5)

3.4

(1.2

9.7

)

Dea

th fr

om c

ardi

ovas

-cu

lar

caus

es, n

on-

fata

l MI,

or s

trok

e

6 (0

.9)

15 (

2.2)

20 (

3.0)

35 (

2.6)

2.9

7.3

9.9

8.6

2.5

(1.0

6.4

)3.

4 (1

.48

.5)

2.9

(1.2

7.0

)

Dea

th fr

om c

ardi

ovas

-cu

lar

caus

es, n

on-

fata

l MI,

stro

ke,

or h

eart

failu

re

7 (1

.0)

16 (

2.3)

23 (

3.4)

39 (

2.9)

3.4

7.8

11.4

9.6

2.3

(0.9

5.5

)3.

4 (1

.47

.8)

2.8

(1.3

6.3

)

Dea

th fr

om c

ardi

ovas

-cu

lar

caus

es, n

on-

fata

l MI,

stro

ke, h

eart

fa

ilure

, or

angi

na

11 (

1.6)

18 (

2.6)

25 (

3.7)

43 (

3.2)

5.4

8.7

12.5

10. 6

1.6

(0.8

3.4

)2.

3 (1

.14

.7)

2.0

(1.0

3.8

)

Dea

th fr

om c

ardi

ovas

-cu

lar

caus

es, n

on-

fata

l MI,

stro

ke, h

eart

fa

ilure

, or

angi

na

or n

eed

for

a ca

rdio

-va

scul

ar p

roce

dure

17 (

2.5)

26 (

3.8)

31 (

4.6)

57 (

4.2)

8.4

12.7

15.5

14.1

1.5

(0.8

2.8

)1.

9 (1

.03

.3)

1.7

(1.0

2.9

)



n engl j med

352;11

www.nejm.org march

17

,

2005

The

new england journal

of

medicine

1076

boxane A

2

, which promotes platelet aggregation,vasoconstriction, and smooth-muscle proliferation,is synthesized primarily in platelets, which expressonly COX-1. Conversely, prostacyclin, which has an-tiaggregative, antiproliferative, and vasodilatory ac-tions, is the main prostanoid product of endothelialcells, synthesized as a result of the action of COX-2.

22

Whereas nonselective NSAIDs inhibit both

COX-1 and COX-2, selective COX-2 inhibitors actprimarily on COX-2.

9

The selective COX-2 inhibi-tors may therefore suppress vascular productionof prostacyclin without affecting the synthesis ofplatelet-derived thromboxane A

2

. This imbalancemay promote thrombosis and increase the risk ofcardiovascular events.

10

Nonaspirin, nonselectiveNSAIDs may also not sufficiently reduce throm-boxane A

2

synthesis long enough to prevent plate-let aggregation and atherosclerotic events.

10

Otherpotentially detrimental effects of COX-2 inhibi-tors have been suggested, including elevated bloodpressure, though some reports have indicated thatthese drugs may have beneficial effects on vascu-lar health.

23

In contrast to our findings, most of the earlierclinical trials of selective COX-2 inhibitors in pa-tients with arthritis did not appear to show an in-crease in cardiovascular risk.

2,5,14,24

These trials,

however, were generally short-term studies designedto assess the use of this class of drug for pain reliefand to evaluate associated adverse gastrointestinalevents. They included a relatively small proportionof patients at high risk for cardiovascular events orexcluded such patients, despite the fact that manypatients who are taking these drugs or who are con-sidered candidates for this therapy are at high car-diovascular risk.

25

Consequently, the studies lackedadequate statistical power to confirm or refute a car-diovascular hazard related to the use of COX-2 in-hibitors.

11

The use of active rather than placebo con-trols in many of these studies also made the findingsdifficult to interpret.

The results of the Vioxx Gastrointestinal Out-comes

Research (VIGOR) trial

3

and a subsequentstudy, APPROVe,

26

raised questions about the safetyof rofecoxib. The VIGOR trial, which compared anine-month course of 50 mg of rofecoxib per day(a larger dose than that usually recommended forthe long-term treatment of arthritis) with naproxenin patients with rheumatoid arthritis, reported ahigher risk of myocardial infarction among the pa-tients receiving rofecoxib.

27

Some have attributedthese findings to the potentially cardioprotective ef-fects of naproxen,

28,29

although this interpretationhas been a source of contention.

18,20

Table 3. Incidence of Individual Cardiovascular and Fatal Events.

End PointPlacebo (N=679)



Both Celecoxib Groups (N=1356)

number of patients (percent)

Death from any cause 6 (0.9) 6 (0.9) 9 (1.3) 15 (1.1)

Death from cardiovascular causes 1 (0.1) 3 (0.4) 6 (0.9) 9 (0.7)

Death from noncardiovascular causes 5 (0.7) 3 (0.4) 3 (0.4) 6 (0.4)

Nonfatal cardiovascular events

Myocardial infarction 3 (0.4) 9 (1.3) 9 (1.3) 18 (1.3)

Stroke 3 (0.4) 3 (0.4) 5 (0.7) 8 (0.6)

Heart failure 2 (0.3) 1 (0.1) 4 (0.6) 5 (0.4)

Thromboembolic event 1 (0.1) 3 (0.4) 4 (0.6) 7 (0.5)

Resuscitation after sudden cardiac arrest

0 0 1 (0.1) 1 (0.1)

Hospitalization for unstable angina

5 (0.7) 4 (0.6) 2 (0.3) 6 (0.4)

Arrhythmia 9 (1.3) 4 (0.6) 7 (1.0) 11 (0.8)

Cardiovascular procedure 7 (1.0) 9 (1.3) 6 (0.9) 15 (1.1)

Other 9 (1.3) 11 (1.6) 14 (2.1) 25 (1.8)



n engl j med

352;11

www.nejm.org march

17, 2005


1077

More recently, the APPROVe trial, a randomized,placebo-controlled trial designed to evaluate the ef-ficacy of rofecoxib for preventing colorectal polypsin patients with a history of colorectal adenomas,was terminated early because of an increased riskof cardiovascular events.

10,26

These results prompt-ed voluntary withdrawal of rofecoxib from the mar-ket. Topol reported that another controlled trial alsoshowed an increased risk of cardiovascular eventswith treatment with 12.5 mg of rofecoxib per day,as compared with nabumetone or placebo.

30

The results of other studies have aroused con-cern about the safety of selective COX-2 inhibitors.In a placebo-controlled trial of pain relief after cor-onary-artery bypass surgery, the use of the paren-teral COX-2 inhibitor parecoxib followed by oraltreatment with its active metabolite valdecoxib, ortreatment with placebo followed by valdecoxib, wasassociated with a significantly increased risk of car-diovascular thromboembolic events.

31

In this issueof the

Journal,

Nussmeier et al. report a second trialshowing a significant increase in cardiovascularevents when parecoxib and valdecoxib were used inthe immediate postoperative period after coronary-artery bypass surgery.

32

The Therapeutic ArthritisResearch and Gastrointestinal Event Trial (TARGET)also showed a nonsignificant increase in the risk ofcardiovascular events with lumiracoxib therapy,

10

ascompared with naproxen or ibuprofen therapy, butonly among patients who were not taking aspirin.

In contrast, to our knowledge, neither phar-macoepidemiologic studies nor randomized, con-trolled trials have reported clear evidence of anincreased cardiovascular risk associated with cele-coxib. The failure of pharmacoepidemiologic stud-ies to show an increased risk may be due in part tothe lower doses and shorter duration of use in thesestudies than in clinical trials and in part to the po-tential for selection bias in nonrandomized studies.Nevertheless, the Celecoxib in Long-term ArthritisSafety Study (CLASS),

2

which used the same doseof celecoxib (400 mg twice daily) that was given toone group in the APC study and compared celecoxibwith two nonselective NSAIDs, did not show an in-creased rate of cardiovascular events.

2

CLASS dif-fered from the VIGOR study in several importantways. A short-term study not designed for system-atic and formal assessment of cardiovascularevents, CLASS enrolled relatively low-risk patientsand allowed the use of aspirin for cardiovascularprotection. In addition, FitzGerald has suggestedthat CLASS did not completely refute evidence of

an increased cardiac risk associated with celecoxibuse in nonaspirin users, as compared with thosetaking ibuprofen (but not diclofenac).

20

Moreover,the results of a randomized, controlled clinical trialof celecoxib in patients with Alzheimers disease,reported to the Food and Drug Administration,demonstrated an increase in cardiovascular eventsamong patients receiving celecoxib.

33

Although we found that patients with an in-creased cardiovascular risk at baseline appeared tohave a higher absolute rate of events than those withno increase in cardiovascular risk at baseline, for-mal statistical tests of interaction showed no dif-ferential effect of celecoxib with respect to baselinecardiovascular risk. One prespecified subgroup in-cluded users of cardioprotective aspirin at base-line. Although the overall absolute risk appeared tobe higher among such patients, analysis of the dataon aspirin users in this study shows that they had ahigher frequency of cardiovascular risk factors atbaseline than did nonusers.

The cardiovascular findings with regard to cele-coxib use in the APC study are consistent with thoseidentified for rofecoxib use in the APPROVe trial. Incontrast, preliminary analyses from the PreSAP trial,which involved a daily dose of 400 mg of celecoxib,showed no apparent increase in cardiovascular risk.The differences in the dosing regimens betweenthese two trials twice daily in the APC study, as

Figure 1. KaplanMeier Estimates of the Risk of the Composite End Point of Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart Failure among Patients Who Received Celecoxib (200 mg Twice Daily or 400 mg Twice Daily) or Placebo.

The log-rank statistic of 8.73, which has two degrees of freedom, was used to determine the P value.

Estim

ated

Pro

babi

lity

of C

ompo

site

End

Poi

nt

0.0500.0450.040

0.0300.025

0.0100.015

0.005

0.035

0.020

0.0000 6 12 18 24 30 36

Months after First Dose

No. at RiskCelecoxib, 400 mg Celecoxib, 200 mg Placebo

648 670 667

576 595 585

651 673 668

665 676 675

655 675 672

669 681 677

671685679

P=0.01

Placebo

Celecoxib, 400 mg

Celecoxib, 200 mg



n engl j med

352;11

www.nejm.org march

17

,

2005

The

new england journal

of

medicine

1078

compared with once daily in the PreSAP study support the hypothesis that sustained inhibition ofprostacyclin may contribute to the increase in car-diovascular risk. Other potential differences in thetrials, including geographic differences, differencesin the patient population, and differences in use ofconcomitant medications, may have contributed tothe disparity in the preliminary findings.

The increased cardiovascular risk in the APC trialwas based on a small number of events in a trial thatwas not designed or statistically powered to evalu-ate cardiovascular risk. Although we believe we haveidentified all adverse cardiovascular events, we can-not rule out the possibility that some events re-mained unreported. Our results must therefore beinterpreted with caution.

Still, in the context of the results of the other tri-als reviewed involving agents in the same class,these data suggest that there may be a real increasein cardiovascular risk associated with the use of cele-coxib in particular and the class of selective COX-2inhibitors in general. If correct, this interpretation

has substantial implications for public health,

11,34

patient education,

35

and drug regulation.

36,37

Giventhe experience with COX-2 inhibitors, we supportthe call for regulatory agencies to consider request-ing a formal evaluation of long-term cardiovascu-lar outcomes of any new drug with a mechanism ofaction that could augment the risk of cardiac andvascular events, especially if many patients who arelikely to use the new agent are prone to cardiovas-cular disease.

25

This category may include nonse-lective NSAIDs (other than aspirin), as discussedearlier. More broadly, this experience underscoresboth the need for long-term, placebo-controlled tri-als to assess safety as well as efficacy and the needto improve methods for assessing potential adversecardiovascular outcomes in studies with noncar-diovascular primary end points.

In summary, a blinded review of cardiovascularevents in a large, randomized, controlled study oftwo doses of celecoxib for the prevention of colorec-tal adenomas showed a dose-related risk of suchevents, including death from cardiovascular causes,

* CI denotes confidence interval.

Table 4. Incidence of Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart Failure According to Baseline Characteristics.

SubgroupNo. of

Patients PlaceboBoth Celecoxib

GroupsHazard Ratio

(95% CI)*P Value for Interaction

no./total no. (%)

Age 0.61

n engl j med

352;11

www.nejm.org march

17, 2005


1079

myocardial infarction, stroke, and heart failure. Inlight of other recent reports of the adverse cardio-vascular effects of other agents in this class, thesedata provide further evidence that long-term use ofCOX-2 inhibitors may increase the risk of seriouscardiovascular events. These risks will need to beweighed against any potential benefits of celecox-

ib in preventing colorectal neoplasia and in reliev-ing pain.

The APC was sponsored by the National Cancer Institute and co-sponsored by Pfizer. This cardiovascular review was funded solely bythe National Cancer Institute.

Drs. McMurray, Pfeffer, and Zauber report having received con-sulting fees from Pfizer. Drs. Solomon, McMurray, and Pfeffer re-port having received lecture fees from Pfizer. Dr. Wittes reports hav-ing received consulting fees from Merck within the past two years.

appendix

The following persons participated in the APC Study:

Steering Committee:

M.M. Bertagnolli, E. Hawk, C. Eagle;

Statistical Team:

A. Zaub-er, K.M. Kim, D. Corle, R. Rosenstein, J. Tang, T. Hess, A. Wilton;

Medical Monitors:

W. Anderson, L. Doody;

Central Pathology Review:

M.Redston;

Project Directors

: M. Woloj, D. Bagheri, A. Crawford, M. Schietrum, V. Ladouceur;

Data and Safety Monitoring Board

: S. Rosen(chair), L. Friedman, R. Makuch, R. Phillips, P. Taylor;

Principal Investigators: United States:

S. Auerbach (California Professional Re-search, Newport Beach), C.F. Barish (Wake Research Associates, Raleigh, N.C.), T. Barringer (Carolinas Medical Center, Charlotte, N.C.),R.W. Bennetts (Northwest Gastroenterology Clinic, Portland, Oreg.), M. Blitstein (Associates in Gastroenterology and Liver Disease, LakeForest, Ill.), J. Bruggen (Wake Forest University Baptist Medical Center, Winston-Salem, N.C.), P. Carricaburu (Veterans Affairs Hospital,Sheridan, Wyo.), D. Chung (Massachusetts General Hospital, Boston), F. Colizzo (Pentucket Medical Associates, Haverhill, Mass.), R. Cur-tis (NewtonWellesley Hospital, Newton, Mass.), T. Dewar (Harris Methodist Hospital Fort Worth, Ft. Worth, Tex.), R. DuBois (VanderbiltUniversity Medical Center, Nashville), T. Feinstat (Gastroenterology Consultants of Sacramento, Roseville, Calif.), T.R. Foley (RegionalGastroenterology Associates of Lancaster, Lancaster, Pa.), D. Gabbaizadeh (Huntington Research Group, Huntington Station, N.Y.), J.Geenen (Wisconsin Center for Advanced Research, Milwaukee), F. Giardiello (Johns Hopkins Hospital, Baltimore), A. Goetsch (nTouch Re-search, Huntsville, Ala.), M. Goldberg (Regional Gastroenterology Associates of Lancaster, Evanston, Ill.), J.L. Goldstein (University of Illi-nois at Chicago, Chicago), W. Harlan, III (Asheville Gastroenterology Associates, Asheville, N.C.), R. Hogan (Gastrointestinal Associates,Jackson, Miss.), M. Kamionkowski (Gastroenterology Associates of Cleveland, Mayfield Heights, Ohio), M. Kelfer (Fallon Clinic, WestBoylston, Mass.), B. Kerzner (Health Trends Research, Baltimore), K. Kim (University of Chicago Medical Center, Chicago), I. Klimberg(Gastroenterology Associates of Ocala, Ocala, Fla.), G. Koval (West Hills Gastroenterology Associates, Portland, Oreg.), C. Krone (Ad-vanced Clinical Therapeutics, Tucson, Ariz.), S. Krumholz (Waterside Clinical Research, West Palm Beach, Fla.), M.W. Layton (South PugetSound Clinical Research Center, Olympia, Wash.), C. Lightdale (Columbia-Presbyterian Medical Center, New York), P.J. Limburg (MayoClinic, Rochester, Minn.), C. Lind (Vanderbilt University Medical Center, Nashville), D. Lipkis (Institute for Health Care Assessment, SanDiego, Calif.), M. Lloyd (Idaho Gastroenterology, Meridian), D. Maccini (Spokane Digestive Disease Center, Spokane, Wash.), F. MacMilan,Sr. (Pentucket Medical Associates, Haverhill, Mass.), R. Madoff (University of Minnesota, Minneapolis), A. Malik (Advanced Clinical Re-search, North Providence, R.I.), A. Markowitz (Memorial Sloan-Kettering Cancer Center, New York), R. Marks (Alabama Digestive Re-search Center, Alabaster), C.J. McDougall (Manhattan Associates, New York), P. Miner (Oklahoma Foundation for Digestive Research,Oklahoma City), M. Murphy (Southeastern Digestive and Liver Disease Institute, Savannah, Ga.), A. Namias (Gastrointestinal Physicians,Salem, Mass.), N. Nickl (University of Kentucky Medical Center, Lexington), M. Pochapin (Jay Monahan Center for Gastrointestinal Health,New York), R.E. Pruitt (Nashville Medical Research Institute, Nashville), J. Puolos (Cumberland Research Associates, Fayetteville, N.C.),D.S. Riff (AGMG Clinical Research, Anaheim, Calif.), R. Roman (South Denver Gastroenterology, Englewood, Colo.), L. Rubin (New JerseyPhysicians, Passaic), D. Ruff (Healthcare Discoveries, San Antonio, Tex.), M. Safdi (Consultants for Clinical Research, Cincinnati), J. Saltz-man (Brigham and Womens Hospital, Boston), B. Salzberg (Atlanta Gastroenterology Associates, Atlanta), J.A. Sattler (Western ClinicalResearch, Torrance, Calif.), P. Schleinitz (Americas Doctors Research, Medford, Oreg.), J. Schwartz (Northwest Gastroenterologists, Ar-lington Heights, Ill.), M. Schwartz (Jupiter Research Association, Jupiter, Fla.), M. Silpa (Gastroenterology Associates of The East Bay Med-ical Group, Berkeley, Calif.), D. Silvers (Drug Research Services, Metairie, La.), D. Smoot (Howard University Cancer Center, Washington,D.C.), S. Sontag (Veterans Affairs Medical Center, Hines, Ill.), R.J. Sorrell (Gastroenterology Specialties, Lincoln, Nebr.), D. Stanton (Com-munity Clinical Trials, Orange, Calif.), J. Sturgeon (Americas Doctors Research, Shawnee Mission, Kans.), J.P. Tracey (Hawthorne MedicalAssociates, North Dartmouth, Mass.), T. Werth (Charlotte Gastroenterology and Hepatology, Charlotte, N.C.), C.M. Wilcox (University ofAlabama at Birmingham, Birmingham), R. Wohlman (Northwest Gastroenterology Associates, Bellevue, Wash.), S. Woods (Gastroenter-ology Associates of Fairfield County, Bridgeport, Conn.);

United Kingdom:

J. Burn (South Cleveland Hospital, Middlesbrough);

Australia:

H. Ee (Sir Charles Gairdner Hospital, Nedlands, W.A.), M. Korman (Monash Medical Centre, Clayton, Victoria), A. Lee (Concord Repatria-tion and General Hospital, Concord, N.S.W.), B. Leggett (Royal Brisbane Hospital, Herston, Queensland), F. Macrae (Royal MelbourneHospital, Melbourne, Victoria), L. Mollison (Freemantle Hospital, Freemantle, W.A.), N. Yeomans (Western Hospital, Footscray, Victo-ria), G. Young (Flinders Medical Centre, Bedford, S.A.);

Canada:

G. Aumais (Hospital Maisonneuve-Rosemont, Montreal), R. Bailey (HysMedical Centre, Edmonton, Alta.), C. Bernstein (Winnipeg Health Sciences Centre, Winnipeg, Man.), L. Cohen (Sunnybrook and Wom-ens Hospital, Toronto), C. Dallaire, R. Dube (Centre Hospitalier Universitaire de Quebec, Quebec, Que.), D. Morgan (McMaster University,Hamilton, Ont.), T. Sylwestrowicz (St. Pauls Hospital, Saskatoon, Sask.), G. Van Rosendaal (University of Calgary Health Sciences Centre,Calgary, Alta.), S.J. Van Zantan (Queen Elizabeth II Health Sciences Centre, Halifax, N.S.).

references

1.

Marnett LJ, Rowlinson SW, GoodwinDC, Kalgutkar AS, Lanzo CA. Arachidonicacid oxygenation by COX-1 and COX-2:mechanisms of catalysis and inhibition.J Biol Chem 1999;274:22903-6.

2.

Silverstein FE, Faich G, Goldstein JL, etal. Gastrointestinal toxicity with celecoxib vsnonsteroidal anti-inflammatory drugs for

osteoarthritis and rheumatoid arthritis: theCLASS study: a randomized controlled trial.JAMA 2000;284:1247-55.

3.

Bombardier C, Laine L, Reicin A, et al.Comparison of upper gastrointestinal toxic-ity of rofecoxib and naproxen in patientswith rheumatoid arthritis. N Engl J Med2000;343:1520-8.

4.

Marnett LJ, Kalgutkar AS. Cyclooxygen-ase 2 inhibitors: discovery, selectivity andthe future. Trends Pharmacol Sci 1999;20:465-9.

5.

Steinbach G, Lynch PM, Phillips RKS, etal. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous poly-posis. N Engl J Med 2000;342:1946-52.



n engl j med

352;11

www.nejm.org march

17

,

2005

1080


6.

Giardiello FM, Yang VW, Hylind LM, etal. Primary chemoprevention of familial ad-enomatous polyposis with sulindac. N EnglJ Med 2002;346:1054-9.

7.

Baron JA. Epidemiology of non-steroi-dal anti-inflammatory drugs and cancer.Prog Exp Tumor Res 2003;37:1-24.

8.

Hawk ET, Viner J, Richmond E, Umar A.Non-steroidal anti-inflammatory drugs(NSAIDs) for colorectal cancer prevention.Cancer Chemother Biol Response Modif2003;21:759-89.

9.

FitzGerald GA, Patrono C. The coxibs,selective inhibitors of cyclooxygenase-2.N Engl J Med 2001;345:433-42.

10.

FitzGerald GA. Coxibs and cardiovascu-lar disease. N Engl J Med 2004;351:1709-11.

11.

Topol EJ, Falk GW. A coxib a day wontkeep the doctor away. Lancet 2004;364:639-40.

12.

White WB, Faich G, Borer JS, MakuchRW. Cardiovascular thrombotic events in ar-thritis trials of the cyclooxygenase-2 inhibi-tor celecoxib. Am J Cardiol 2003;92:411-8.

13.

Mamdani M, Juurlink DN, Lee DS, et al.Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatorydrugs and congestive heart failure outcomesin elderly patients: a population-based co-hort study. Lancet 2004;363:1751-6.

14.

Solomon DH, Schneeweiss S, Glynn RJ,et al. Relationship between selective cyclo-oxygenase-2 inhibitors and acute myocar-dial infarction in older adults. Circulation2004;109:2068-73.

15.

Ray WA, Stein CM, Daugherty JR, HallK, Arbogast PG, Griffin MR. COX-2 selectivenon-steroidal anti-inflammatory drugs andrisk of serious coronary heart disease. Lan-cet 2002;360:1071-3.

16.

Mamdani M, Rochon P, Juurlink DN, etal. Effect of selective cyclooxygenase 2 in-hibitors and naproxen on short-term risk ofacute myocardial infarction in the elderly.Arch Intern Med 2003;163:481-6.

17.

Furberg CD, Psaty BM, FitzGerald GA.

Parecoxib, valdecoxib, and cardiovascularrisk. Circulation 2005;111:249.

18.

Juni P, Nartey L, Reichenbach S, SterchiR, Dieppe PA, Egger M. Risk of cardiovascu-lar events and rofecoxib: cumulative meta-analysis. Lancet 2004;364:2021-9.

19.

Crofford LJ, Lipsky PE, Brooks P,Abramson SB, Simon LS, van de Putte LB.Basic biology and clinical application of spe-cific cyclooxygenase-2 inhibitors. ArthritisRheum 2000;43:4-13.

20.

FitzGerald GA. COX-2 and beyond: ap-proaches to prostaglandin inhibition in hu-man disease. Nat Rev Drug Discov 2003;2:879-90.

21.

McAdam BF, Catella-Lawson F, MardiniIA, Kapoor S, Lawson JA, FitzGerald GA.Systemic biosynthesis of prostacyclin by cy-clooxygenase (COX)-2: the human pharma-cology of a selective inhibitor of COX-2. ProcNatl Acad Sci U S A 1999;96:272-7. [Erra-tum, Proc Natl Acad Sci U S A 1999;96:5890.]

22.

Brock TG, McNish RW, Peters-GoldenM. Arachidonic acid is preferentially metab-olized by cyclooxygenase-2 to prostacyclinand prostaglandin E2. J Biol Chem 1999;274:11660-6.

23.

Chenevard R, Hurlimann D, Bechir M,et al. Selective COX-2 inhibition improvesendothelial function in coronary artery dis-ease. Circulation 2003;107:405-9.

24.

Farkouh ME, Kirshner H, HarringtonRA, et al. Comparison of lumiracoxib withnaproxen and ibuprofen in the TherapeuticArthritis Research and GastrointestinalEvent Trial (TARGET), cardiovascular out-comes: randomised controlled trial. Lancet2004;364:675-84.

25.

Zhao SZ, Burke TA, Whelton A, von All-men H, Henderson SC. Comparison of thebaseline cardiovascular risk profile amonghypertensive patients prescribed COX-2-specific inhibitors or nonspecific NSAIDs:data from real-life practice. Am J ManagCare 2002;8:Suppl:S392-S400.

26.

Bresalier RS, Sandler RS, Quan H, et al.Cardiovascular events associated with rofe-coxib in a colorectal adenoma chemopreven-tion trial. N Engl J Med 2005;352:1092-102.

27.

Mukherjee D, Nissen SE, Topol EJ. Riskof cardiovascular events associated with se-lective COX-2 inhibitors. JAMA 2001;286:954-9.

28. Weir MR, Sperling RS, Reicin A, GertzBJ. Selective COX-2 inhibition and cardio-vascular effects: a review of the rofecoxib de-velopment program. Am Heart J 2003;146:591-604.29. Konstam MA, Weir MR, Reicin A, et al.Cardiovascular thrombotic events in con-trolled, clinical trials of rofecoxib. Circula-tion 2001;104:2280-8.30. Topol EJ. Rofecoxib, Merck, and theFDA. N Engl J Med 2004;351:2877-8.31. Ott E, Nussmeier NA, Duke PC, et al. Ef-ficacy and safety of the cyclooxygenase 2 in-hibitors parecoxib and valdecoxib in pa-tients undergoing coronary artery bypasssurgery. J Thorac Cardiovasc Surg 2003;125:1481-92.32. Nussmeier NA, Whelton AA, BrownMT, et al. Complications of the COX-2 inhib-itors parecoxib and valdecoxib after cardiacsurgery. N Engl J Med 2005;352:1081-91.33. Celecoxib. PhRMA IQ5-97-02-001. (Ac-cessed February 18, 2005, at http://www.clinicalstudyresults.org/documents/company-study_76_0.pdf.)34. Topol EJ. Failing the public health rofecoxib, Merck, and the FDA. N Engl J Med2004;351:1707-9.35. Dieppe PA, Ebrahim S, Martin RM, JuniP. Lessons from the withdrawal of rofecox-ib. BMJ 2004;329:867-8.36. Josefson D. FDA warns Merck over itspromotion of rofecoxib. BMJ 2001;323:767.37. Mukherjee D, Topol EJ. Pharmaceuticaladvertising versus research spending: areprofits more important than patients? AmHeart J 2003;146:563-4.Copyright 2005 Massachusetts Medical Society.



Documents

nejmoa050405